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WO2006046916A1 - Nouveaux derives de sulfonamide utilises comme modulateurs du recepteur glucocorticoide et destines au traitement de maladies inflammatoires - Google Patents

Nouveaux derives de sulfonamide utilises comme modulateurs du recepteur glucocorticoide et destines au traitement de maladies inflammatoires Download PDF

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Publication number
WO2006046916A1
WO2006046916A1 PCT/SE2005/001610 SE2005001610W WO2006046916A1 WO 2006046916 A1 WO2006046916 A1 WO 2006046916A1 SE 2005001610 W SE2005001610 W SE 2005001610W WO 2006046916 A1 WO2006046916 A1 WO 2006046916A1
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WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
phenyl
haloalkyl
methyl
Prior art date
Application number
PCT/SE2005/001610
Other languages
English (en)
Inventor
Håkan BLADH
Krister Henriksson
Vijaykumar Hulikal
Matti Lepistö
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0402636A external-priority patent/SE0402636D0/xx
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU2005300150A priority Critical patent/AU2005300150A1/en
Priority to BRPI0517263-2A priority patent/BRPI0517263A/pt
Priority to CA002584413A priority patent/CA2584413A1/fr
Priority to US11/718,214 priority patent/US20090093485A1/en
Priority to RSP-2007/0076A priority patent/RS20070076A/sr
Priority to EP05796607A priority patent/EP1807391A4/fr
Priority to MX2007004862A priority patent/MX2007004862A/es
Publication of WO2006046916A1 publication Critical patent/WO2006046916A1/fr
Priority to IL182685A priority patent/IL182685A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to sulphonamide derivatives, to their use as medicaments (for example in the treatment of an inflammatory disease state), to pharmaceutical compositions comprising them and to processes for preparing them.
  • Sulphonamide derivatives are disclosed as antiinflammatories in WO 2004/019935 and WO 2004/050631.
  • Pharmaceutically active sulphonamides are also disclosed in Arch. Pharm. (1980) 313 166-173, J.Med. Chem. (2003) 46 64-73, J. Med. Chem (1997) 40 996- 1004, EP 0031954, EP 1190710 (WO 200124786), US 5861401, US 4948809, US3992441 and WO 99/33786.
  • non-steroidal compounds interact with the glucocorticoid receptor (GR) and, as a result of this interaction, produce a suppression of inflammation (see, for example, US6323199).
  • GR glucocorticoid receptor
  • Such compounds can show a clear dissociation between anti ⁇ inflammatory and metabolic actions making them superior to earlier reported steroidal and non-steroidal glucocorticoids.
  • the present invention provides further non-steroidal compounds as modulators (for example agonists, antagonists, partial agonists or partial antagonists) of the glucocorticoid receptor capable of having a dissociation between their anti-inflammatory and metabolic actions.
  • the present invention provides a compound of formula (I):
  • A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkylthio, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C(O)(C 1-4 alkyl), C(O)NH 2 , C(O)NH(C
  • R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are, independently, hydrogen, C 1-4 alkyl or C 3-7 cycloalkyl;
  • R 1 is hydrogen, Ci -6 alkyl, phenyl, pyridinylC(O), C 3-6 cycloalkyl, (C 3-6 cycloalkyl)CH 2 or C 3- 4 alkenyl;
  • L is a bond, C 1-4 alkylene (optionally substituted by C 1-4 alkyl or C 1-4 haloalkyl), C 1-4 alkylene-NH (optionally substituted by C 1-4 alkyl or C 1-4 haloalkyl), CH 2 C(O)NH, CH(CH 3 )C(O)NH, Ci -4 alkylene-0 (optionally substituted by C 1-4 alkyl or C 1-4 haloalkyl), C 1 - 4 alkylene-S (optionally substituted by C 1-4 alkyl or C 1-4 haloalkyl), Ci -4 alkylene-S(O) (optionally substituted by Ci -4 alkyl or C 1-4 haloalkyl) or C 1-4 alkylene-S(O) 2 (optionally substituted by C 1-4 alkyl or Ci -4 haloalkyl);
  • W is cyclohexyl, phenyl, methylenedioxyphenyl, thienyl, pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl, [l,6]-naphthi
  • W is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkylthio, C 1-4 fluoroalkyl, C 1 . 4 fluoroalkoxy, nitro, cyano, OH, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(Ci -4 alkyl) 2 , benzyloxy, imidazolyl, C(O)(Ci -4 allcyl), C(O)NH 2 , C(O)NH(Ci -4 alkyl), C(O)N(Ci -4 alkyl) 2 , NHC(O)(Ci -4 alkyl) OrNR 12 R 13 ; R 12 and R 13 are, independently, hydrogen, Ci -4 alkyl or C 3-7 cycloal
  • Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate, p- toluenesulphonate, succinate, glutarate or malonate.
  • the compounds of formula (I) may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl.
  • Haloalkyl comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 halogen (such as fluorine or chlorine) atoms. It is, for example, CHF 2 , CF 3 , CH 2 CF 3 , C 2 F 5 or CH 2 Cl.
  • Haloalkoxy comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 halogen (such as fluorine or chlorine) atoms. It is, for example, OCHF 2 , OCF 3 , OCH 2 CF 3 , OC 2 F 5 or OCH 2 Cl.
  • Fluoroalkyl comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 fluorine atoms. It is, for example, CHF 2 , CF 3 , CH 2 CF 3 or C 2 F 5 .
  • Fluoroalkoxy comprises, for example, 1 to 6, such as 1, 2, 3, 4 or 5 fluorine atoms. It is, for example, OCHF 2 , OCF 3 , OCH 2 CF 3 or OC 2 F 5 .
  • Cycloalkyl is for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • the present invention provides a compound of formula (I), wherein A is phenyl, naphthyl, pyridinyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkylthio, CF 3 , OCF 3 , pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (Ci -4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C(O)(Cj -4 alkyl), C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(Cj
  • the present invention provides a compound of formula (I), wherein A is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, Ci -6 alkyl, Ci -6 alkoxy, Ci -4 alkylthio, CF 3 , OCF 3 , phenoxy (optionally substituted by halo or Ci -4 alkyl), phenyl (optionally substituted by halo or Ci -4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O) 2 NH 2 , C(O)(C 1-4 alkyl), C(O)NH 2 , NHC(O)(C 1-4 alkyl) or NR 10 R 11 ; R 10 and R 11 are, independently, hydrogen, Cj -4 alkyl or C 3-7 cycloalkyl; R 1 is hydrogen, Ci -6 alkyl, phenyl,
  • the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo (such as fluoro, chloro or bromo), Cj -6 alkyl, C 1-6 alkoxy, nitro, phenoxy (optionally substituted by C 1-4 alkyl), phenyl (optionally substituted by halo (such as fluoro)), pyridinyloxy Or N(C 1-4 alkyl) 2 ; R 1 is hydrogen, C 1-6 alkyl, phenyl, pyridylC(O), cyclohexyl, cyclohexylCH 2 or C 3-4 alkenyl, L is a bond, C 1-4 alkylene (optionally substituted by C 1-4 alkyl), C 1-4 alkylene-NH (optionally substituted by C 1-4 alkyl), CH 2 C
  • the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, Ci -4 alkylthio, CF 3 , OCF 3 , pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C(O)(C 1-4 alkyl), C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(Ci -4 alkyl
  • the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, Ci -6 alkoxy, C 1-4 alkylthio, CF 3 , OCF 3 , phenoxy (optionally substituted by halo or C 1-4 alkyl), phenyl (optionally substituted by halo or C 1-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O) 2 NH 2 , C(O)(C 1-4 alkyl), C(O)NH 2 , NHC(O)(C 1-4 alkyl) or NR 10 R 11 ; R 10 and R 11 are, independently, hydrogen, C 1-4 alkyl or C 3-7 cycloalkyl; R 1 is hydrogen, Ci -6 alkyl, phenyl
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, Ci -4 alkyl, C 1-4 haloalkyl, Ci -4 alkoxy or Ci -4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci -4 alkyl, C 1-4 haloalkyl, Ci -4 alkoxy or C 1-4 haloalkoxy) or pyrazolyl (optionally substituted by C 1-4 alkyl, C 1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, Ci -4 alkoxy or C 1-4 haloalkoxy)).
  • the invention provides a compound of formula (I) wherein L is C 3 alkylene (substituted by Ci -4 alkyl or Ci -4 haloalkyl), C 2-4 alkylene-NH (substituted by Ci -4 alkyl or C 1-4 haloalkyl), CH 2 C(O)NH, CH(CH 3 )C(O)NH, C 2-4 alkylene-0 (substituted by C 1-4 alkyl or Ci -4 haloalkyl), C 2-4 alkylene-S (substituted by Ci -4 alkyl or Ci -4 haloalkyl), C 2-4 alkylene-S(O) (optionally substituted by Ci -4 alkyl or Ci -4 haloalkyl) or C 2-4 alkylene-S(O) 2 (optionally substituted by C 1-4 alkyl or C 1-4 haloalkyl); wherein C 1-4 alkyl is, for example, methyl or ethyl;
  • the invention provides a compound of formula (I) wherein L is C 3 alkylene (substituted by C 1-4 alkyl or Cj -4 haloalkyl), C 2-4 alkylene-NH (substituted by C 1-4 alkyl or C 1-4 haloalkyl) or C 2-4 alkylene-0 (substituted by C 1-4 alkyl or Ci -4 haloalkyl); wherein C 1-4 alkyl is, for example, methyl or ethyl; and C 1-4 haloalkyl is, for example, CF 3 .
  • the invention provides a compound of formula (I) wherein L is C 3 alkylene (substituted by Ci -4 alkyl), C 2 alkylene-NH (substituted by Ci -4 alkyl) or C 2 alkylene- O (substituted by Cj -4 alkyl); wherein Ci -4 alkyl is, for example, methyl or ethyl.
  • L is, for example, C 2 alkylene-NH (substituted by Ci -4 alkyl).
  • L is, for example, C 2 alkylene-0 (substituted by Ci -4 alkyl).
  • the invention provides a compound of formula (I) wherein L is CH(CH 3 )CH 2 CH 2 (such as in the S-configuration), CH(CH 3 )CH 2 NH (such as in the S- configuration), CH(CH 3 )CH 2 O (such as in the S -configuration), CH(C 2 H 5 )CH 2 CH 2 (such as in the S-configuration), CH(C 2 H 5 )CH 2 NH (such as in the S-configuration), CH(C 2 H 5 )CH 2 O (such as in the S-configuration) or CH(CF 3 )CH 2 CH 2 (such as in the S-configuration).
  • the present invention provides a compound of formula (I) wherein L is CH(CH 3 )CH 2 NH (such as in the S-configuration) or it provides a compound of formula (I) wherein L is CH(CH 3 )CH 2 O (such as in the S-configuration).
  • the present invention provides a compound of formula (I) wherein W is phenyl, pyridyl, indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol- 7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl).
  • W is phenyl, pyridyl, indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol- 7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol
  • the present invention provides a compound of formula (I) wherein W is indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinolinyl (for example isoquinolin-5-yl).
  • W is indolyl (for example indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), indazolyl (for example indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl), quinolinyl (for example quinolin-5-yl) or isoquinol
  • the present invention provides a compound of formula (I) wherein W is indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, indazol-4-yl, indazol-5-yl, indazol- 6-yl, indazol-7-yl, quinolin-5-yl or isoquinolin-5-yl.
  • the present invention provides a compound of formula (I) wherein W is indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl or quinolin-5-yl.
  • W is optionally substituted by halogen, C 1-4 alkyl, CF 3 , Ci -4 alkoxy, OCF 3 , phenyl (itself optionally substituted by halogen, Ci -4 alkyl, CF 3 , C 1-4 alkoxy or OCF 3 ) or C(O)NH 2 .
  • the present invention provides a compound of formula (I) wherein L is C 1-4 alkylene (optionally substituted by Cu 4 alkyl) or Ci -4 alkylene-0 (optionally substituted by C 1-4 alkyl); for example L is CH(CH 3 )CH 2 O, CH 2 CH 2 O, CH(CH 3 )(CH 2 ) 2 or
  • L is C 1-4 alkylene (optionally substituted by Ci -4 alkyl) or C 1-4 alkylene-0 (optionally substituted by Ci -4 alkyl).
  • the present invention provides a compound of formula (I) wherein R 1 is hydrogen.
  • the present invention provides a compound of formula (I) wherein W is methylenedioxyphenyl, benzofuranyl, benzthienyl, indolyl, indolinyl, dihydroindolinyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, [l,8]-naphthiridinyl or [l,6]-naphthiridinyl, optionally substituted as defined above.
  • W is linked to L by a ring-carbon in the benzene ring part of its structure (see for example, Example 77, 78, 79, 80 or 83).
  • the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl or thienyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkylthio, CF 3 , OCF 3 , phenoxy (optionally substituted by halo or C 1-4 alkyl), phenyl (optionally substituted by halo or C 1-4 alkyl), pyridinyloxy, benzyloxy, nitro, cyano, S(O) 2 NH 2 , C(O)(C 1-4 alkyl), C(O)NH 2 , NHC(O)(Ci -4 alkyl) OrNR 10 R 11 ; R 10 and R 11 are, independently, hydrogen, C 1-4 alkyl or C 3-7 cycloalkyl; R 1 is hydrogen; L is C 1-4 alkylene (optionally substituted by Ci -4 alkyl) or C
  • the present invention provides a compound of formula (I) wherein: A is phenyl, naphthyl or thienyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , OCF 3 , phenoxy (optionally substituted by halo or Ci -4 alkyl), phenyl (optionally substituted by halo or Ci -4 alkyl), pyridinyloxy, nitro or cyano; R 1 is hydrogen; L is C 1-4 alkylene (optionally substituted by C 1-4 alkyl) or C 1-4 alkylene-0 (optionally substituted by C 1-4 alkyl); W is phenyl optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , OCF 3 , nitro or cyano; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkylthio, C 1-4 fluoroalkyl, C 1-4 fiuoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C(O)(C 1-4 alkyl),
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C 1-4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxy or Ci -4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci -4 alkyl, Ci -4 haloalkyl, C 1-4 alkoxy or Ci -4 haloalkoxy) or pyrazolyl (optionally substituted by Ci -4 alkyl, Ci -4 haloalkyl or phenyl (itself optionally substituted by halogen, C 1-4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxy or C 1-4 haloalkoxy)); R 1 is hydrogen; L is C 3 alkylene (substituted by C 1-4 alkyl or Ci -4 haloalkyl), C 2- 4 alkylene-NH (substituted by Ci -4 alkyl
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or Ci -4 haloalkoxy), pyridyl (optionally substituted by halogen, Ci -4 alkyl, Ci -4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci -4 alkyl, Ci -4 haloalkyl or phenyl (itself optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy)); R 1 is hydrogen; L is C 3 alkylene (substituted by C 1-4 alkyl or C 1-4 haloalkyl), C 2- 4 alkylene-NH (substituted by C 1-4 alky
  • the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, C 1-6 aikoxy, C 1-4 alkylthio, C M fluoroalkyl, C 1-4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C(O)(C 1-4 alkyl),
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, Ci -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C 1-4 alkyl, Ci -4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy) or pyrazolyl (optionally substituted by Ci -4 alkyl, Ci -4 haloalkyl or phenyl (itself optionally substituted by halogen, Ci -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy)); R 1 is hydrogen; L is CH(CH 3 )CH 2 CH 2 (such as in the S-configuration), CH(CH 3 )CH 2 NH (such as in the S-configuration), CH(CH 3 )CH 2 O (
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C 1-4 alkyl, Ci -4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, Ci -4 alkoxy or C 1-4 haloalkoxy) or pyrazolyl (optionally substituted by C 1-4 alkyl, C 1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or Ci -4 haloalkoxy)); R 1 is hydrogen; L is CH(CH 3 )CH 2 CH 2 (such as in the S-configuration), CH(CH 3 )CH 2 NH (such as in the S-configuration), CH(CH 3 )CH 2 O
  • the present invention provides a compound of formula (I) wherein A is phenyl, naphthyl, pyridinyl, furyl, thienyl, isoxazolyl, pyrazolyl, benzthienyl, quinolinyl or isoquinolinyl, and A is optionally substituted by halo, C 1-6 alkyl, Ci -6 alkoxy, C 1-4 alkylthio, Ci -4 fluoroalkyl, Ci -4 fluoroalkoxy, pyridinyloxy, benzyloxy, nitro, cyano, C(O) 2 H, C(O) 2 (C 1-4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Ci -4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C(O)(C 1-4 alkyl), C(O)NH 2 , C(O)
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, Ci -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy) or pyrazolyl (optionally substituted by C 1-4 alkyl, Ci -4 haloalkyl or phenyl (itself optionally substituted by halogen, Ci -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy)); R 1 is hydrogen; L is CH(CH 3 )CH 2 NH (such as in the S-configuration) or L is CH(CH 3 )CH 2 O (such as in the S-configuration); W is phenyl,
  • the present invention provides a compound of formula (I) wherein A is phenyl (optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy), pyridyl (optionally substituted by halogen, C 1-4 alkyl, Q -4 haloalkyl, Ci -4 alkoxy or Ci -4 haloalkoxy) or pyrazolyl (optionally substituted by Ci -4 alkyl, C 1-4 haloalkyl or phenyl (itself optionally substituted by halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy)); R 1 is hydrogen; L is CH(CH 3 )CH 2 NH (such as in the S -configuration) or L is CH(CH 3 )CH 2 O (such as in the S-configuration); W is indazol
  • the present invention provides a compound: 4-Bromo-N-( 1 -methyl-3-phenyl-propyl)-benzenesulfonamide; 4-Chloro-N-( 1 -methyl-3-phenyl-propyl)-benzenesulfonamide; 4-Bromo-2-methyl-N-(l-methyl-3-phenyl-propyl)-benzenesulfonamide; N-(I -Methyl-3 -phenyl-propyl)-4-trifluoromethoxy-benzenesulfonamide; 4-Methoxy-2,3 ,6-trimethyl-N-( 1 -methyl-3 -phenyl-propyl)-benzenesulfonamide; 4-tert-Butyl-N-(l-methyl-3-phenyl-propyl)-benzenesulfonamide; N-(l-Methyl-3-phenyl-propyl)-4-phenoxy-benzenes
  • Naphthalene-2-sulfonic acid [2-(2,6-dimethyl-phenoxy)- 1 -methyl-ethyl]-amide
  • Naphthalene-2-sulfonic acid (3-phenyl-propyl)-amide
  • the compounds of formula (I) can be prepared using or adapting methods disclosed in the art, or by using or adapting the method disclosed in the Examples below.
  • Starting materials for the preparative methods are either commercially available or can be prepared by literature methods, adapting literature methods.
  • a compound of the invention can be prepared by coupling a compound of formula (II):
  • Y is a leaving group (for example chlorine), with a compound of formula (III):
  • N-L-W (in) ⁇ in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide
  • a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide
  • the invention further provides processes for the preparation of the compounds of formula (I). Because of their ability to bind to the glucocorticoid receptor the compounds of formula (I) are useful as anti-inflammatory agents, and can also display antiallergic, immunosuppressive and antiproliferative actions.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can be used as a medicament for the treatment or prophylaxis of one or more of the following pathologic conditions (disease states) in a mammal (such as a human): (i) Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes:
  • collagen diseases of other origins for example systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis
  • Gastrointestinal diseases which coincide with inflammatory, allergic and/or proliferative processes:
  • otitis externa for example caused by contact dermatitis, infection, etc.
  • cerebral edema mainly tumor-induced cerebral edema
  • the compounds of formula (I) can also be used to treat disorders such as: Conies Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's Syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, oesophageal varicies, Addison's Disease, muscle weakness, increased melanin pigmentation of the skin, weight loss, hypotension, hypoglycemia, Cushing's Syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, poly
  • CHF congestive heart failure
  • 'congestive heart disease refers to a disease state of the cardiovascular system whereby the heart is unable to efficiently pump an adequate volume of blood to meet the requirements of the body's tissues and organ systems.
  • CHF is characterized by left ventricular failure (systolic dysfunction) and fluid accumulation in the lungs, with the underlying cause being attributed to one or more heart or cardiovascular disease states including coronary artery disease, myocardial infarction, hypertension, diabetes, valvular heart disease, and cardiomyopathy.
  • diastolic congestive heart failure refers to a state of CHF characterized by impairment in the ability of the heart to properly relax and fill with blood.
  • systolic congestive heart failure refers to a state of CHF characterized by impairment in the ability of the heart to properly contract and eject blood.
  • physiological disorders may present as a “chronic” condition, or an “acute” episode.
  • chronic means a condition of slow progress and long continuance.
  • a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease.
  • acute means an exacerbated event or attack, of short course, followed by a period of remission.
  • the treatment of physiological disorders contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear.
  • the present invention provides the use of a compound or formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy (such as a therapy described above).
  • the present invention provides the use of a compound or formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a glucocorticoid receptor mediated disease state (such as a disease state described above).
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an inflammatory (such as an arthritic) condition.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an asthmatic or dermatological condition.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of COPD.
  • the present invention further provides a method of treating a glucocorticoid receptor mediated disease state in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for the therapeutic treatment of a mammal, said active ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, (active ingredient) and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention provides a process for the preparation of said composition comprising mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition can comprise from 0.05 to 99 %w (per cent by weight), for example from 0.05 to 80 %w, such as from 0.10 to 70 %w (for example from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition.
  • a pharmaceutical composition of the present invention can be administered in a standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • a the compound of formula (I), or a pharmaceutically acceptable salt thereof may be formulated into the form of, for example, an aerosol, a powder (for example dry or dispersible), a tablet, a capsule, a syrup, a granule, an aqueous or oily solution or suspension, an (lipid) emulsion, a suppository, an ointment, a cream, drops, or a sterile injectable aqueous or oily solution or suspension.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule containing between O.lmg and Ig of active ingredient.
  • composition of the invention is one suitable for intravenous, subcutaneous, intraarticular or intramuscular injection.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art. Tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • the invention further relates to combination therapies or compositions wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states.
  • a compound of the invention can be combined with a TNF- ⁇ inhibitor (such as an anti-TNF monoclonal antibody (such as Remicade, CDP- 870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-I / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin), a COX-2 inhibitor (such as mel
  • the present invention still further relates to the combination of a compound of the invention together with:
  • a leukotriene biosynthesis inhibitor such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, an N-(5-substituted)-thiophene-2- alkylsulfonamide, a 2,6-di-tert-butylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591, MK-886 or BAY x 1005;
  • a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTD.sub4. or LTE.sub4. selected from the group consisting of a phenothiazin-3-one such as L- 651,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIIL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro- 245913, iralukast (CGP 45715A) or BAY x 7195;
  • a phenothiazin-3-one such as L- 651,392
  • an amidino compound such as CGS-25019c
  • a benzoxalamine such as ontazolast
  • a PDE4 inhibitor including an inhibitor of the isoform PDE4D
  • an antihistaminic H.subl . receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; a gastroprotective H.sub2.
  • an ⁇ .subl.- and ⁇ .sub2.- adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride; an anticholinergic agent such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; a ⁇ .subl.- to ⁇ .sub4.-adrenoceptor agonist (such as ⁇ 2 adrenoceptor agonist) such as metaproterenol, isoproterenol, isoprenaline, albuterol, sal
  • MMP- 13 collagenase-3
  • MMP-3 stromelysin- 1
  • MMP-10 stromelysin-2
  • MMP-I l stromelysin-3
  • MMP-12 a modulator of chemokine receptor function such as CCRl, CCR2, CCR2A, CCR2B,
  • CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl for the C-C family
  • CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 for the C-X-C family
  • CX 3 CRl for the C-X 3 -C family
  • an osteoporosis agent such as raloxifene, droloxifene, lasofoxifene or fosomax
  • an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate
  • a compound useful in the treatment of AIDS and/or HIV infection for example: an agent which prevents or inhibits the viral protein gpl20 from engaging host cell CD4
  • ⁇ such as soluble CD4 (recombinant); an anti-CD4 antibody (or modified / recombinant antibody) for example PRO542; an anti-groupl20 antibody (or modified / recombinant antibody); or another agent which interferes with the binding of group 120 to CD4 for example BMS 806 ⁇ ; an agent which prevents binding to a chemokine receptor, other than CCR5, used by the HIV virus ⁇ such as a CXCR4 agonist or antagonist or an anti-CXCR4 antibody ⁇ ; a compound which interferes in the fusion between the HIV viral envelope and a cell membrane ⁇ such as an anti- group 41 antibody; enfuvirtide (T-20) or T- 1249 ⁇ ; an inhibitor of DC-SIGN (also known as CD209) ⁇ such as an anti-DC-SIGN antibody or an inhibitor of DC-SIGN binding ⁇ ; a nucleoside/nucleotide analogue reverse transciptase inhibitor ⁇ for example zidovudine
  • the present invention still further relates to the combination of a compound of the invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin- B.subl. - and B.sub2.
  • a -receptor antagonist comprising: (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGF ⁇ ); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK.
  • an anti-gout agent e.g., colchicine
  • NKP-608C sub 1. and NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418;
  • an elastase inhibitors selected from the group consisting of UT- 77 and ZD-0892;
  • TACE TNF ⁇ converting enzyme inhibitor
  • iNOS induced nitric oxide synthase inhibitor
  • a chemoattractant receptor-homologous molecule expressed on TH2 cells a CRTH2 antagonist.
  • NMP l-Methyl-2-pyrrolidinone app approximately sat saturated aq aqueous
  • Method A Instrument Agilent 1100; Column C 18 Waters Symmetry 2.1 x 30 mm 3.5 ⁇ m; Flow rate 0.7 ml/min; Mass APCI; UV-absorption was measured at 254nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 5-95%/B 8 min, 95% B 2 min.
  • Method B Instrument Agilent 1100; Column Kromasil C 18 3 x 100 mm 5 ⁇ m; Flow rate 1.0 ml/min; UV-absorption was measured at 254nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 10-100%B 20 min, 100% B 1 min.
  • Examples 18 - 76 were synthesised by a method analogous to that described in Example 17 using the corresponding starting materials.
  • Step 1 (2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate
  • Step 2 N-[(l S)-2-(5-Isoquinolinyloxy)- 1 -methylethyl]-2,4,6-trimethylbenzenesulfonamide (2S)-2-[(Mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (263mg, O. ⁇ mmole) was added to a slurry containing Cs 2 CO 3 (487mg, 1.5mmole) and 5- Hydroxyisoquinoline (145mg, lmmole) in 2.5mL DMF.
  • reaction mixture was stirred overnight in room teperature before it was diluted with ethyl acetate (2OmL) and washed with lMHCl/aq. The organic layer was dried, concentrated and purified on HPLC-C 18 .
  • Examples 78 - 83 were synthesised by a method analogous to that described in Example 77 using (2S)-2-[(mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate and the corresponding starting materials.
  • Examples 85-95 were synthesised by a method analogous to that described in Example 84 using the corresponding starting materials.
  • Phthalic anhydride (50mmole, 7.4g) was dissolved in 10OmL toluene together with L- alaninol (50mmole, 3.9mL) and DIEA (5mmole, 900 ⁇ L). The mixture was refluxed with continues removal of water with a Dean-Stark apparatus for two hours before it was washed with IM HCl/aq , sat. NaHCO 3 /aq. The organic layer was dried, concentrated and used in the next step without any further purification. APCI-MS m/z: 206.0 [MH+].
  • Examples 97 - 122 were synthesised by a method analogous to that described in Example 96 using the corresponding starting materials.
  • Examples 124 — 129 were synthesised by a method analogous to that described in Example 123 using the corresponding starting materials.
  • Examples 131-144 were prepared via the aryl ether formation as described in Example 4, using (2S)-2-[(mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate and the orresponding starting materials.
  • TBAT (Llmmole, 594mg) was dissolved in dry THF (12mL) and cooled to 0 0 C under iert conditions.
  • 4-methyl-N-[(lZ)-3-phenylpropylidene]- enzenesulfonamide (1 mmole, 287mg) and trimethyl(trifluoromethyl)silane (1.2mmole, 70mg) were dissolved in dry THF (1OmL) and slowly added to the TBAT-solution. The lixture was stirred for 45 min at 0°C before it was quenched with sat. NH 4 Cl/aq (6mL) . At Dom temperature the mixture was extracted with ethylacetate. The organic phase was dried, oncentrated and purified on a silica gel column chromatography (heptane-ethyl acetate).
  • Examples 147 to 153 were synthesised by a method analogous to that described in ⁇ xample 146 using the corresponding starting materials.
  • Examples 154 to 158 were synthesised by a method analogous to that described in ⁇ xample 96, "Sulfonamide coupling", using the corresponding starting materials. cample 154 -(2-AnilmoethylV2,4,6-trimetliylbenzenesulfonamide
  • Example 160 was synthesised using a method analogous to Example 159.
  • the title compound was obtained from 2-mesitylenesulfonyl chloride, 2-aminobutan- -ol and quinolin-5-ol by a method analogous to that described in Example 77.
  • Examples 164 - 184 were synthesised by a method analogous to that described in ⁇ xample 17 using the corresponding starting materials.
  • Examples 186- 194 were synthesised by a method analogous to that described in Example 185 using the corresponding starting materials.

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Abstract

L'invention concerne des composés de formule (I) ou un sel pharmaceutiquement acceptables desdits composés. Elle concerne des compositions contenant ces composés, des méthodes de préparation de ces composés et l'utilisation de ces composés dans un traitement médical, tel que la modulation du récepteur glucocorticoïde chez un animal à sang chaud.
PCT/SE2005/001610 2004-10-29 2005-10-26 Nouveaux derives de sulfonamide utilises comme modulateurs du recepteur glucocorticoide et destines au traitement de maladies inflammatoires WO2006046916A1 (fr)

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AU2005300150A AU2005300150A1 (en) 2004-10-29 2005-10-26 Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases
BRPI0517263-2A BRPI0517263A (pt) 2004-10-29 2005-10-26 novos derivados de sulfonamida como moduladores do receptor de glicocorticóide para o tratamento de doenças inflamatórias
CA002584413A CA2584413A1 (fr) 2004-10-29 2005-10-26 Nouveaux derives de sulfonamide utilises comme modulateurs du recepteur glucocorticoide et destines au traitement de maladies inflammatoires
US11/718,214 US20090093485A1 (en) 2004-10-29 2005-10-26 Novel Sulphonamide Derivatives as Glucocorticoid Receptor Modulators for the Treatment of Inflammatory Diseases
RSP-2007/0076A RS20070076A (en) 2004-10-29 2005-10-26 Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases
EP05796607A EP1807391A4 (fr) 2004-10-29 2005-10-26 Nouveaux derives de sulfonamide utilises comme modulateurs du recepteur glucocorticoide et destines au traitement de maladies inflammatoires
MX2007004862A MX2007004862A (es) 2004-10-29 2005-10-26 Nuevos derivados de sulfonamida como moduladores del receptor de glucocorticoides para el tratamiento de enfermedades inflamatorias.
IL182685A IL182685A0 (en) 2004-10-29 2007-04-19 Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases

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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007100851A1 (fr) * 2006-02-28 2007-09-07 Helicon Therapeutics, Inc. Composes therapeutiques
WO2008010765A1 (fr) 2006-07-19 2008-01-24 Astrazeneca Ab Nouveaux composés
WO2008063116A1 (fr) * 2006-11-23 2008-05-29 Astrazeneca Ab Dérivés d'indozalyl sulfomnamide utiles comme modulateurs des glucocorticoïdes
WO2008076048A1 (fr) * 2006-12-21 2008-06-26 Astrazeneca Ab Dérivés d'amide et d'ester d'indazolyle pour traiter des troubles médiés par le récepteur de glucocorticoïde
WO2008075005A1 (fr) 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique
WO2008079073A1 (fr) * 2006-12-22 2008-07-03 Astrazeneca Ab Dérivés de l'indazolyl sulfonamide pour le traitement des affections induites par les récepteurs des glucocorticoïdes
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AU2005300150A1 (en) 2006-05-04
EP1807391A1 (fr) 2007-07-18
MX2007004862A (es) 2007-05-09
TW200630326A (en) 2006-09-01
PA8651001A1 (es) 2006-06-02
PE20060932A1 (es) 2006-10-13
UY29182A1 (es) 2006-05-31
IL182685A0 (en) 2007-09-20
RS20070076A (en) 2008-09-29
KR20070068432A (ko) 2007-06-29
EP1807391A4 (fr) 2010-01-06
BRPI0517263A (pt) 2008-10-07
ECSP077349A (es) 2007-04-26
US20090093485A1 (en) 2009-04-09
CR9022A (es) 2007-10-04
CA2584413A1 (fr) 2006-05-04
GT200500307A (es) 2006-06-06

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